Dragee preparation and apparatus therefor



y 1968 P. RIECKMANN ET AL 3,381,659

DRAGEE PREPARATION AND APPARATUS THEREFOR 2 Sheets-Sheet Original FiledJan. 16

INVENTORS: PfTEK RIECKM/W/V HH/VZ SCH/MK B KK/ /ARQwT/MEL Y 15 w, m L WW ATTORA EYS y 7, 1963 P. RIECKMANN ET AL 3,381,659

DRAGEE PREPARATION AND APPARATUS THEREFOR 2 Sheets-Sheet 2 OriginalFiled Jan. 16, 1965 USE.

DRYER f5 TIMER FUSE E g I -46 \NVENTORS:

United States Patent 4 Claims. (61. 11s 19 ABSTRACT OF THE DISCLOSUREImprovements in the apparatus for use in the automatic production ofdrages comprising a rotatable coating kettle for holding pill centers tobe coated, spray 20 means for delivering coating suspension from asupply tank Onto said pill centers, means for delivering heated gas ontosaid pill centers and means for exhausting heated gas, the improvementin combining the aforesaid components with a gear pump, a safety valve,a solenoid steered three-way valve and specifically associated conduitsinterrelating them all so that the spraying period, the inactive periodand the drying period are automatically controlled, the amount ofsuspension to be delivered being directly controlled by the control ofthe spraying period.

The instant application is a continuation-in-part of application Ser.No. 331,639 filed Dec. 5, 1963 and now abandoned which is a division ofapplication Ser. No. 252,275, filed Jan. 16, 1963 and now abandoned.

The present invention relates to a process for the manufacture of dragesand to an apparatus therefor. In one aspect it relates to an automaticprocess for rapidly manufacturing pharmaceutically acceptable drages.

It is known that the drage represents one of the most wide-spread formsin which drugs are administered, and that the administration of drugs inthis form is growing in popularity. Drage preparations are characterizedby the advantages that they are easy to ingest and eliminate the badtaste which is characteristic of so many drugs. Furthermore, the drageis a particularly important vehicle for use in connection with drugswhich are sensitive to light, air, and moisture. Still further in thecase of drugs which have a disturbing effect on the stomach or which areinactivated in the stomach, special coatings can be applied so that thedrage will not dissolve until it reaches the intestines, resulting inexcellent tolerability and permitting the oral administration of drugsnot possible in the absence of such coatings.

The manufacture of drages suitable for commercial utilization involvesmany diificulties. As heretofore carried out, it is a manual artrequiring much practice, skill, and experience. The pill or centercoming from the tablet forming machine has first applied thereto whereneces- 6O sary, isolation coatings which act to protect thepharmaceutical substances from external influences. The pill or centeris then coated with a sugar syrup of a certain composition andthereafter with mixtures of talc, chalk and like solid fillers. Thisprocess has to be repeated several times in order to apply to the pillas quickly as possible SllfilClfilllI material to produce on the drage,edges which are rounded. However, the surface of the pill so obtained isnot smooth and has to be smoothed out in further steps, using thereforboth sugar syrups and powdered sugar. The smoothing step is followed bycoloring steps, whereby a uniformly colored drage is achieved onlyfollowing the application of many coats of colored sugar syrup. Finallythe drages are waxed or glazed. Between each of the individual steps inthe process, the drages are taken from the coating treatment kettle anddried in large drying machines or ovens so that the moisture necessaryin connection with the coating applications cannot penetrate through thecovering and damage the drugs forming the center or core.

The process as described above requires a great deal of hand work byexperienced personnel. A particularly serious disadvantage is the needto keep the drages in motion in the kettle by stirring them by handuntil they no longer stick to one another or to the kettle. Anotherdifiiculty lies in that the process consumes an enormous amount of time.The drages are required to spend a total of about two days time in thekettle with additional time for periodic interruptions required fordrying between each step in the process. In all a total of 8 to 10 daysproduction time is required for producing each batch of drages.

Methods for rapidly coating pills have become known in recent years inconnection with which it has been proposed that all of the substances tobe applied to the pills be combined in a single, sugar-coatingsuspension. Such a process has, for example, been described in GermanPatent 1,000,569 and is carried out using a coating suspensionconsisting of water, sugar, starch and sodium cellulose glycolate withheat. While this process has been somewhat successful, it has not gainedwide-spread usage as it produces satisfactory results only if thecoating process is constantly supervised (see Gstirner, Grundstoffe undVerfahren der Arzneibereitung, Verlag F. Enke, Stuttgart 1960, page 61).The constant supervision required represents a considerable disadvantagein comparison with the conventional coating process describedhereinbefore in which the kettles do not have to be kept under constantsupervision and observation.

Other rapid coating processes have been proposed which are based uponthe complete elimination of the use of sugar, the coating beingperformed, for example, using alcoholic solutions of polyethylene glycol(see Gstirner, loc. cit., page 62). Polyethylene glycols, however, havethe significant shortcoming that they are particularly bad tasting. Theuse of drages produced with alcoholic solutions of polyethylene glycolis disagreeable to the patient and therefore do not otter the advantagesassociated with this form of drug administration.

It is accordingly the general object of the present invention to providea method for the manufacture of drages which are of a purity, surfacesmoothness, taste, and color suitable for commercial use, in aneconomically feasible manner.

Another object of the invention is to provide a method for themanufacture of drages which are of a purity, surface smoothness, taste,and color which makes their use convenient and inexpensive without anydisagreeableness to the patient who has to take repeated doses of thepharmaceutical contained in the drage.

Still another object of the invention is to provide a substantiallyautomatic method for the manufacture of drages.

Still another object of the invention is to provide a rapid method forthe manufacture of drages.

Still a further object of the invention is to provide an apparatus forthe manufacture of drages which are of a purity, surface smoothness,taste, and color suitable for commercial use.

It is still another object of the invention to provide drages, i.e. animproved vehicle for therapeutic compositions being characterized bystability, surface smoothness, pleasant taste, etc., and whereby thefull effect of the therapeutic mechanism can be carried out when thecomposition is administered orally.

Still a further object of the invention is to provide coat ingsuspensions for coating dr'ages, containing polythe kettle to the dryingoven and back which represents a serious disadvantage of the coatingprocesses as conventionally practiced is eliminated. A furtherconsiderable advantage of the instant process is that the time requiredethylene glycol in addition to sugar and filler materials for productionof a batch of drages amounts to only in aqueous suspension. about oneday. In connection with the production time,

Still another object of this invention is to provide an it should benoted that the capacity per kettle is many apparatus for the manufactureof drages which delivers times that of the conventionally practicedprocess. Thus, an exactly controlled amount of coating suspension at anywhereas in the known conventional method, the kettle predetermined timeonto pill centers moving in a rotatable 1O charge was limited to thatamount which could be kept coating kettle. broken up and moving by hand,the kettle in accordance Other and further objects and advantages of theinwith the invention can be filled to its maximum capacity. vention willbecome apparent to one skilled in the art A special advantage stemmingfrom the process of the inupon referring to the accompanying disclosureand the vention lies in the fact that each coating which is applieddrawing in which: is a relatively thin coating, is dried immediately andcon- FIG. 1 is a schematic illustration of a preferred emsequently nopenetration of moisture into the center durbodiment of the apparatus ofthe invention. ing the coating process takes place. Since smoothcoatings FIG. 2 is a further schematic illustration of the emare formedfrom the start, the total or over-all coating bodiment shown in FIG. 1showing the combination can also be much thinner than usual. Thecoatings in with a pump, an electrically steered three-way valve, andaccordance with the invention amount to approximately an overpressurevalve connected with a spray nozzle and up to 1 /2 times the weight ofthe center where formerly a source of coating suspension and theinterconnecting the coatings amounted to about twice the weight of theconduits. center.

FIG. 3 is a diagrammatic representation of the wiring The coatingsuspensions of the invention per se are of an embodiment of theapparatus shown in FIG. 2. novel and can be produced very simply withoutheat mere- In accordance with the present invention a fully autoly bystirring the components together and homogenizing matic rapid method forthe production of drages eharthe resultant suspension, for example, in acorrundum acterized by pleasant taste, smoothness of surface and diskmill or the like. In Table l, which follows, illustraperfect color hasnow been found. It has been found active examples of a number of coatingsuspensions according to the invention that when pill centers or corescording to the present invention are set out. It is possible are coatedusing an aqueous-sugar coating suspension conin accordance with theinvention to add coloring material taining, 1-10 weight percent ofpolyethylene glycol in from the start of the process if desired, thusachieving a addition to -50 weight percent of sugar and l020 uniformcoloration of the d-rages.

TABLE 1 Example 1 2 3 4 5 6 7 8 9 10 Sugar Carbowax 6000 (arhowax 20.000 Starch Syrup Gum Arabic Chalk Titanium oxide Triealcium phosphateColoring 2 Water to make.

1 Trade name of polyethylene glycol.

2 q.s. =quantum sullicit.

weight percent of solid fillers, drages are obtained characterized bythe properties as just set out. In preparing the drage, the coatingsuspension is sprayed onto the pills or centers maintained in rotationin a coating kettle, the spraying interrupted and the sprayed dragecenters maintained in rotation for a period of time and thereafter thecoated centers dried with a current of warm air. These three steps inthe sequence as set out are repeated, if necessary, until the desiredtotal amount of coating suspension has been applied.

In this way and namely by the incorporation according to the inventionof a small amount of polyethylene glycol in a sugar-containing coatingsuspension, the tendency to stickiness at the start of the drying of thesuspension is overcome, that is the drages do not stick to one anothernor do they adhere to the kettle wall. There is, as a result, madepossible a rapid, fully automatic pill center coating process. Theinvention makes possible for the first time the possibility in a singleoperation to apply the coating suspension onto the pill center and todry the same thereon. In the process as herein taught, the need forhandwork is eliminated other than that which is required for adjustingthe equipment at the beginning and at the end of the process. Further,the requirement for experienced technicians to carry out the process iseliminated. Furthermore, drying ovens are no longer required whereby thefrequent transporting of the drages from The following examplesillustrate satisfactory procedures for the manufacture of drages, but itis to be understood that they are presented only for the purpose ofillustration and not as indicating the limits of the invention.

Example 1 8 kilograms of drage centers of 6 mm. diameter (weight ofcenters mg, number of centers 100,000) were introduced into a kettlehaving a 60 cm. diameter provided with a powerful exhaust system. Thecoating kettle was not provided with any bafiles or like constructionand had a substantially smooth, even, continuous, imperforate innersurface. The spraying system was adjusted so that about 80ml. of thecoating suspension were sprayed onto the centers within a period of 25seconds in each of the coating steps. The centers were circulated, i.e.rotated for 1.5 minutes following the spraying without any externalinterference so that the suspension could be uniformly distributed onthe surface of the drages. The batch was then dried with a current ofhot air for 2 minutes. These three steps were repeated until 8.5 kg. ofsuspension had been applied. The coating suspension employed was one inaccordance with the invention containing polyethylene glycol in additionto sugar and solid fillers. The drages which had smooth coatings fromthe start of the procedure were then ready for waxing. The

total production time amounted to about 6.5 to 7 hours and nosupervision of any kind was required in this period. After the coatinghad been completed, the drages had a weight of 130 mg. The coatingdissolved in the Erweka disintegration tester in about 4 minutes and wascomparable with a very good candy coating as formed by the process asused hitherto.

Examples 25 The process of Example 1 was repeated, the data and resultsof these coating operations carried out in accordance with the processof the invention are set out in Table 2 which follows:

TABLE 2 Drage Centers 1 Spray Coating The rapid, fully automatic processof, the invention can preferably be carried out using the novelapparatus taught in accordance with the invention.

Referring to FIG. 1, the apparatus according to the inventon which isparticularly suitable for carrying out the fully automatic coatingprocess consists of four separate systems:

(A) A spraying system composed of a spraying nozzle 1 which is connectedby conduit 3, suitable valves or pumping switches 2 to a supply tank 4containing the coating suspension;

(B) A source of heated air 6 provided with suitable switches andconduits 5 and 9 respectively,

(C) An electrical control apparatus composed of a timer mechanism 7, and

(D) An unmodified coating pan 12 mounted on a coating pan motor housing13 provided with the standard means for rotataion, equipped with apowerful exhaust system and filled with pill centers 11. The system A, Band C are mounted for movement by means of wheels 14. The system Dconstitutes an apparatus well known in the pharmaceutical industry foruse in manual coating processes and does not require any furtherequipment or modification.

As can be seen from FIG. 2, as soon as switch 27 is closed, a certainamount of the coating suspension is fed continuously either from thevessel 21 by means of pump 22 to the spray nozzle 25 via conduits 38 and37 or is carried back through an over-pressure valve 26 via conduit 36to the vessel 21. Depending on the switching position of theelectrically controlled three-way valve 23, the suspension either entersthe outer chamber 32 of the three-way valve 23 and leaves it at themiddle chamber 33 for introduction into the spray nozzle 25 or returnsfrom the spray nozzle 25 via the middle chamber 33 and the outer chamber34 to the vessel 21, thereby releasing the pressure within the conduit37 via recycle conduits 35 and 36 back toward the vessel 21. Theconnection of the three-way valve 23 with the conduits 35, 37 and 38 ishighly unusual, because the outlet 29 of the middle chamber 33 generallyis an inlet, whereas the inlet of the outer chamber 32 generally is anoutlet. The timer 28 controls (a) The switching position of the threewayvalve by means of a solenoid, and

(b) The source of warm air, for example a dryer 24,

as soon as the main switch 27 is closed. Depending on the switchingposition of the threeway valve 23, the middle chamber 33 is eitherconnected with the outer chamber 32 or with the outer chamber 34.

The wiring diagram showing the relationship of the timer 28 to theremaining apparatus of FIG. 2 is shown in FIG. 3. The motor 42 of thepump 22 works continuously as soon as the safety switch 41 is closed,whereas the switches 44 and 44' are controlled by the timer 45. Theswitch 44 controls the three-way valve 46 by means of a solenoid,whereas the switch 44' controls the source of heated gas, for example adryer 47, as soon as the main switch 43 is closed. It is advisable tohave separate fuses 48 for the motor 42, the dryer 47 and the solenoid.

The entire apparatus is composed of a number of parts known per so,however, the very specific combination and interrelation of these partsresults in a very reliable and safe apparatu for use in automaticallycoating drages, particularly when using the coating suspension asdescribed herein. In order to assure that an absolutely perfect coatingof the pill centers takes place, the amount of the coating suspension,which i to be delivered onto the pill centers must be exactly controlledby the time of and for delivery of the suspension. This can be achievedby using a conventional spray gun as for example used in spray painting.The advantage of using a spray gun of thi type is based on the fact thatit is provided with a proportioning valve so that different amounts ofcoating suspension can be delivered at a constant time setting. Adisadvantage, however, is that compressed air is required to be usedtherewith resulting in the formation of mist and vapors which must beremoved from the system through an exhaust line; the mist and vaporsrepresenting suspension not deposited on the drages and lost theprocessing. Another disadvantage is that spray guns are not self-feedingso that the coating suspension has to be fed positively to the gun, as,for example by gravity, i.e. from the supply vessel downwardly throughsuitable conduit to the gun.

For these reasons, it has proven advantageous to supply the coatingsuspension at a constant pressure of approximately 10 atmospheres usingtherefor a gear pump. As shown in FIG. 2 the coating suspension suppliedfrom vessel 21 is permanently maintained under pressure within conduit38 and the outer chamber 32 of the three-way valve 23, as soon as theswitch 27 for the motor of the pump 22 is closed. The safety valve 26maintains the pressure at 10 atmospheres and releases the rest of thesuspension backwards to the vessel 21 via conduit 36. If the solenoidhas steered the three-way valve 23 as positioned in FIG. 2, the coatingsuspension can flow into the middle chamber 33 and from there viaconduit 37 to the spray nozzle 25. As the pressure of 10 atmospheres hasalready been built up within the system 38 and 32, the pressure isavailable at the spray nozzle 25 very quickly, when the timer signalsthe order to spray. When the timer signals the order for stopping thespraying, the middle chamber 33 is connected with the outer chamber 34,so that the pressure at the spray nozzle 25 is released immediately viathe conduits 37, 35 and 36 backwards to the vessel 21. It is only withthis specific connection of the valves and the conduits that thepressure at the spray nozzle is available immediately at the beginningand is released immediately at the end of the spraying time.

This effect cannot be achieved if at the beginning or the end of thespraying time a pump is switched on or off respectively, as then thepressure is built up or decreases only slowly. There results, however,no exact spraying at the spray nozzle, if the pressure is less than said10 atmospheres. At for example, 5 atmospheres or at lesser pressure, thesuspension comes out of the spray nozzle in form of drops and dropletsor in form of a beam, so that a uniform distribution of the coatingsuspension onto the pill centers is not possible. According to thisinvention these disadvantages are avoided and it is possible to controlthe exact amount of suspension delivered onto the pill centers bycontrol of time, ie the time and the amount of suspension delivered areexactly proportional.

Although the coating suspension of the invention generally is notinclinded to settle out, it has nevertheless proven advantageous toavoid any possible formation of sediment by agitating the suspension.Due to the circulation produced by the gear pump, via safety valve 26and recycling conduit 36, no additional agitation is required. A furtheradvantage of the apparatus according to this invention is, that nospecial coating pans are necessary and that the old, conventionallypear-shaped rotatable coating pans, which are available in almost everypharmaceutical factory for use in manual coating processes, can be used.Furthermore, it is not necessary to use a pressure tank for the sourceof the coating suspension. Any open vessel can be used, and therefore,if desired or necessary even without interrupting the coating process,the coating suspension can be exchanged or varied.

As a hot air source for small kettles, a hair dryer can be used. Evenfor large kettles, the output of a standard hand dryer is adequate (seeFIGS. 2 and 3). Of course, any other hot air source can be used fordrying as long as it provides the assurance that the temperature andrate of flow of the air are constant.

The timing regulation for the apparatus described above is carried outin the known manner utilizing the conventionally available electricaltimers. These contain, for example, revolving cams which open and closethe necessary contacts. It has proven advantageous, however, to be ableto adjust accurately the spraying time, the inactive period, and thedrying time, and this is done by means of three separate time switchingmechanisms. When separate switching timer mechanisms are used, therunning time can be adjusted during operation which is not directlypossible in the case of cam-operated timers. The spraying system, thepump, the valves, conduits, switches, and the timer, andif desiredeventhe source of hot air of the apparatus described above can be combinedinto a very practical readily movable unit as has been shown in FIG. 1by means of the wheels 14. The apparatus is connected with single-phaseor threephase current source by means of a single cable. If the hot airunit is not built in, a control line isrequired for the hot air inlet.It is an advantage of the apparatus described above, that the movableunit can be removed easily for filling and emptying the coating kettle.

As used herein, and in the claims, the term Carbowax designates thetrade name of a group of non-volatile, solid, polyethylene glycols,soluble in both water and aromatic hydrocarbons and which aremanufactured by Carbide and Carbon Chemical Company, a division of UnionCarbide and Carbon Corporation of New York city, N.Y. Carbowaxes aresupplied in various grades, the grades being designated by numerals asshown in the specification. Increasing grade numbers indicate increasingmolecular weights.

Illustrative examples of the coating suspensions according to thepresent invention have been shown in Table 1. Of course, many changesand variations in the components may be made by those skilled in the artin accordance with the principles set forth herein. Naturally, we makethe limiting statement to the effect that the components of the coatingsuspension must be non-toxic, at least in the amounts in which the sameare employed.

The preferred procedure for the manufacture of drages according to thepresent invention has been shown in Examples 1-5. Of course, manychanges in the reaction conditions, temperature and duration may be madeby those skilled in the art in accordance with the principles set forthherein. The drying of the drages is effected by means of hot air of100-120 C., preferably. In case that the drage center may contain someheat sensitive material, the drying may be effected also at lowertemperatures, whereby the duration of that step will last longer,naturally. In general, the time ranges for each of the steps of thecoating process according to the present invention depend on the size ofthe kettle as well as that of the drage centers, of the humidity of theatmosphere and the like conditions. Preferably, the sprying step has aduration of 550 sec., the pause l0100 sec. and the drying step 50200sec.

The apparatus for effecting the manufacture of the drages according tothe present invention is composed of a number of parts known per se.However, a special arrangement of those componentsas shown in theaccompanying drawings-is necessary to guarantee an absolutely perfectcoating process.

What we claim is:

1. In an apparatus for producing coated pill centers comprising arotatable coating kettle having substantially smooth, even, continuous,imperforate inside surfaces for receiving and holding said pill centers,means for blowing a stream of heated gas onto said pill centers, meansfor exhausing said heated gas after contact thereof with said pillcenters, spray means for delivering a coating suspension composed of avolatile liquid and solid materials onto said pill centers, pump meansfor delivering said suspension from a source containing the same,conduit means connecting said spray means, said pump means and saidsource containing said suspension, said liquid being capable of removaltogether with said heated gas, switch means to control said blowing of astream of heated gas and said spray means, and timing means set tofollow a predetermined cycle, the improvement of combining (a) said pumpmeans with a safety-valve and a recycling conduit for applying apredetermined substantially permanent pressure in said conduit betweensaid pump means and said spray means, and

(b) a solenoid steered three-chambered threeway valve for interruptingthe flow of suspension between said pump means and said spray means at apredetermined time,

(c) conduits interconnecting the middle chamber of said threeway valveas an outlet with said spray means, one of the outer chambers of saidthreeway valve as an inlet for the suspension coming from said pumpmeans, and the other outer chamber thereof with a recycling conduit tosaid source of suspension in order to release backwards that amount ofcompressed suspension which remains within said conduit connecting saidspray means and said threeway valve to the suspension source via aseparate recycling conduit, as soon as the flow of suspension betweensaid pump means and said spray means is interrupted at a predeterminedtime.

2. The improvement in claim 1, wherein at least said gear pump, saidsafety valve, .said three-way valve, said conduits, said spray means,said switch means and said timing means are mounted for movement.

3. In an apparatus for producing coated pill centers comprising acoating kettle for receiving and holding said pill centers, means forblowing a stream of heated gas onto said pill centers, means forexhausting said heated gas after contact thereof with said pill centers,spray means for delivering a coating suspension composed of a solutionand suspended solid materials onto said pill centers, pump means fordelivering said suspension from a source containing the same, conduitmeans connecting said spray means, said pump means and said sourcecontaining said suspension, switch means to control the blowing of saidstream of heated gas and said spray means, and timing means set tofollow a predetermined cycle, the improvement of combining a gear pumpwith a safety valve and a solenoid steered threeway valve forinterrupting the flow of suspension between said gear pump and spraymeans at a predetermined time, said solenoid steered threeway valvehaving three chambers, conduits interconnecting the middle chamber ofsaid threeway valve as an outlet to said spray means, one of the outerchambers of said threeway valve being interconnected by conduits as aninlet for the suspension coming from said gear pump and the other outerchamber of said threeway valve interconnected by conduits with arecycling conduit to said source of suspension wherein said gear pumppumps said suspension against the mechanical force of said safety valvethrough said recycling conduit to said source of suspension.

4. The improvement in claim 3, wherein at least said gear pump, saidsafety valve, said three-way valve, said conduits, said spray means,said switch means and said timing means are mounted for movement.

References Cited UNITED STATES PATENTS 2,551,329 5/1951 Klemola 118-82,652,805 9/1953 DAngelo 118-19 2,810,606 10/1957 Taylor 239-127 X3,095,326 6/1963 Green et al 118-19 X 3,101,040 8/1963 Lanz 118-19 X3,141,792 7/1964 Lachman et al 118-19 X CHARLES A. WILLMUTH, PrimaryExaminer.

J. P. MCINTOSH, Assistant Examiner.

